Abstract The challenges addressed by this R35 application are multiple. First, colorectal cancer (CRC) remains a leading cancer worldwide that is resistant to many treatments. Two important risk factors for CRC are a history of chronic colitis or inflammatory bowel disease (IBD) and obesity, both of which are increasing at an alarming rate. However, the mechanisms linking these predisposing factors to CRC are not well understood and thus there is a pressing need to elucidate these basic mechanisms. Second, obesity is also a contributing factor to other gastrointestinal cancers, where the role of innate immunity receptors is less well-defined than CRC. Understanding the roles of innate immunity in these other cancers is a high priority. Third, the interaction of host genetics, microbiome, inflammation and cellular transformation is complex, but fundamental to the onset of gastrointestinal cancers. Elucidating this network of interaction is important for devising new approaches for cancer therapy. Fourth, while the roles of adaptive immune molecules and cells have been the main stake of cancer immunotherapy, much less emphasis has been placed on innate immune receptors which may alter adaptive immunity to advance cancer immunotherapy, which should be an attractive strategy to combat cancer. Finally, while studies in animals are important in establishing a foundation, a well-defined plan to translate basic findings to humans remains the ultimate goal and challenge that we will address. The NLR (nucleotide-binding domain, leucine-rich repeat containing proteins, or nucleotide-oligomerization domain receptor) is a multi-member gene family that encodes a group of cytosolic proteins that are involved in the intracellular sensing of microbial products as well as damage-associated molecular patterns. NOD2, an NLR family member, has a strong genetic association with Crohns' disease and has been implicated in colitis- associated CRC. Additionally, NLRs including NOD2 and NLRP12 can affect the microbiome to impact colitis in mice, suggesting that NLR family members are important in maintaining or disrupting the homeostasis of gut microbiome. We and others have shown a role for the inflammasome NLRs in models of colitis and CRC. In addition to our analyses of well-studied inflammasome components in models of colitis and CRC, we have been at the forefront of defining a strong role for other NLRs which have anti-inflammatory functions (referred to as inhibitory NLRs), and can alter the course of inflammation and cancer. This proposal plans to examine the roles of NLRs in humans and in murine models of cancers, to elucidate the complex interaction of NLRs with the microbiome and cellular transformation and to harness these proteins to enhance cancer immunotherapy.